Phosphoinositide kinases play central roles in signal transduction by phosphorylating the inositol ring at specific positions. The structure of one such enzyme, type IIb phosphatidylinositol phosphate kinase, reveals a protein kinase ATP-binding core and demonstrates that all phosphoinositide kinases belong to one superfamily. The enzyme is a disc-shaped homodimer with a 33 x 48 A basic flat face that suggests an electrostatic mechanism for plasma membrane targeting. Conserved basic residues form a putative phosphatidylinositol phosphate specificity site. The substrate binding site is open on one side, consistent with dual specificity for phosphatidylinositol 3- and 5-phosphates. A modeled complex with membrane-bound substrate and ATP shows how a phosphoinositide kinase can phosphorylate its substrate in situ at the membrane interface. In the prior year we determined the structure of the adenylyl cyclase core and showed that it consists of a pair of catalytic domains arranged in a wreath. Homologous catalytic domains are arranged in diverse adenylyl and guanylyl cyclases as symmetric homodimers or pseudosymmetric heterodimers. We confirmed the kinship of the adenylyl and guanylyl cyclases by converting photoreceptor guanylyl cyclase into an adenylyl cyclase. We also used site-directed mutagenesis to explore demonstrate the role of Asp-310 in catalytic metal ion binding in the mechanism of type I adenylyl cyclase. In the overall picture of the adenylyl and guanylyl cyclase mechanism, catalysis is activated when two metal-binding Asp residues on one domain are juxtaposed with a key Asn/Arg pair on the other. Allosteric activators of mammalian adenylyl cyclase, forskolin and Gsa, promote the catalytically optimal juxtaposition of the two domains.